作者: Al-Dosari, Mohammed S ; Bushi, Ganesh ; Yadav, Umesh ; Babu, M Arockia ; Gaidhane, Abhay M ; Bansal, Nisha ; Ali, Nemat ; Parvez, Mohammad Khalid ; Singh, Thakur Gurjeet

Renin, an aspartyl protease enzyme, is a crucial part of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. However, numerous renin inhibitors, including Aliskiren, Zankiren, Enalkiren, Fasidotril, and Remikiren, are in the clinical arena of managing hypertension, but they are associated with numerous drawbacks. The important one includes modest efficacy in contrast to other antihypertensive agents, which reduces their use as monotherapy; secondly, the related side effects, including hyperkalemia and renal impairment. Thus, considering the unmet need to identify new renin inhibitors, we applied the drug repurposing technique on an 1880 US FDA-approved small molecules database. The research was achieved by performing the structure-based virtual screening (SBVD) on FDA-approved drugs, which was well supported by molecular docking, dynamics, and mechanics studies. This work identified Panobinostat as a possible lead renin inhibitor. The in vitro Elisa-based assay revealed Panobinostat has the potential to inhibit the renin enzyme at the half-maximal concentration (IC₅₀) of 201.27 nM, while standard renin inhibitor Aliskiren portrayed an IC₅₀ of 162.22 nM. The comparable potency to clinical renin inhibitors presents this HDAC inhibitor as a dual-functioning ligand. The findings are significant and well correlated with the plethora of evidence suggesting the role of HDACs in regulating RAAS and cardiovascular functions via the post-translational level modulation of chromatins' structures and functions.

2015-11-01·Journal of molecular graphics & modelling4区 · 生物学

Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays

4区 · 生物学

Article

作者: Reis, Heribert ; Zerva, Sofia ; Papavasileiou, Konstantinos D ; Alexis, Michael N ; Leonis, Georgios ; Mavromoustakos, Thomas ; Tzoupis, Haralambos ; Peristeras, Loukas D ; Papadopoulos, Manthos G ; Avramopoulos, Aggelos ; Vergadou, Niki ; Czyżnikowska, Żaneta

We investigate the binding mechanism in renin complexes, involving three drugs (remikiren, zankiren and enalkiren) and one lead compound, which was selected after screening the ZINC database. For this purpose, we used ab initio methods (the effective fragment potential, the variational perturbation theory, the energy decomposition analysis, the atoms-in-molecules), docking, molecular dynamics, and the MM-PBSA method. A biological assay for the lead compound has been performed to validate the theoretical findings. Importantly, binding free energy calculations for the three drug complexes are within 3 kcal/mol of the experimental values, thus further justifying our computational protocol, which has been validated through previous studies on 11 drug-protein systems. The main elements of the discovered mechanism are: (i) minor changes are induced to renin upon drug binding, (ii) the three drugs form an extensive network of hydrogen bonds with renin, whilst the lead compound presented diminished interactions, (iii) ligand binding in all complexes is driven by favorable van der Waals interactions and the nonpolar contribution to solvation, while the lead compound is associated with diminished van der Waals interactions compared to the drug-bound forms of renin, and (iv) the environment (H2O/Na(+)) has a small effect on the renin-remikiren interaction.

2012-06-28·Journal of medicinal chemistry1区 · 医学

Dual Inhibitors for Aspartic Proteases HIV-1 PR and Renin: Advancements in AIDS–Hypertension–Diabetes Linkage via Molecular Dynamics, Inhibition Assays, and Binding Free Energy Calculations

1区 · 医学

Article

作者: Supuran, Claudiu T. ; Papadopoulos, Manthos G. ; Leonis, Georgios ; Megariotis, Grigorios ; Tzoupis, Haralambos ; Mavromoustakos, Thomas

Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.

项与占吉仑相关的新闻（医药）

2023-12-15

·SYNAPSE

Understanding Renin Inhibitors and Methods to Keep Abreast of Their Recent Developments

Renin is an enzyme produced and released by the kidneys that plays a crucial role in regulating blood pressure and fluid balance in the human body. It is part of the renin-angiotensin-aldosterone system (RAAS), which helps maintain homeostasis. Renin acts on a protein called angiotensinogen, converting it into angiotensin I. This inactive form is further converted into angiotensin II by other enzymes. Angiotensin II is a potent vasoconstrictor, causing blood vessels to narrow and increasing blood pressure. It also stimulates the release of aldosterone, a hormone that promotes sodium and water retention, further influencing blood pressure and fluid balance. The development of potent inhibitors with acceptable oral bioavailability has been a challenging process since the 1970s. The first and second generations of renin inhibitors faced problems such as poor bioavailability and lack of potency. Finally, the third generation of non-peptidic renin inhibitors was discovered, which had acceptable oral bioavailability and were potent enough for clinical use. The first drug in this class was aliskiren, which received marketing approval in 2007. The analysis of the target renin reveals that Novartis AG is the company with the highest stage of development, with three drugs approved. Hypertension is the most common approved indication for drugs targeting renin. Small molecule drugs and synthetic peptides are the drug types progressing most rapidly. The United States has the highest number of approved drugs, followed by Japan and the European Union. China has shown progress in the development of drugs targeting renin. The competitive landscape for target renin is dynamic, with multiple companies and countries actively involved in research and development. The future development of target renin is expected to continue with a focus on hypertension and other cardiovascular diseases, with potential advancements in drug types and international collaborations. How do they work?Renin inhibitors are a type of medication that target the enzyme renin in the body. Renin is a key component of the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in regulating blood pressure and fluid balance. From a biomedical perspective, renin inhibitors are used in the treatment of hypertension (high blood pressure). By inhibiting the action of renin, these medications help to reduce the production of angiotensin II, a hormone that causes blood vessels to constrict and promotes the release of aldosterone, which leads to increased fluid retention. By blocking the effects of renin, renin inhibitors help to dilate blood vessels and decrease fluid volume, ultimately lowering blood pressure. Some examples of renin inhibitors include aliskiren, the first FDA-approved renin inhibitor, and other newer agents like remikiren and zankiren. These medications are typically prescribed in combination with other antihypertensive drugs to achieve optimal blood pressure control. It is important to note that renin inhibitors should be used under the supervision of a healthcare professional, as they may have potential side effects and can interact with other medications. Regular monitoring of blood pressure and kidney function is typically recommended during treatment with renin inhibitors. List of renin InhibitorsThe currently marketed renin inhibitors include: Aliskiren Hemifumarate/Amlodipine Besilate/HydrochlorothiazideAliskiren Hemifumarate/Amlodipine BesylateAliskiren Hemifumarate/HydrochlorothiazideAliskiren FumarateSPH3127MT-2765Imarikiren hydrochlorideSP-20104(1 A Pharma GmbH)BL-003PRO-20For more information, please click on the image below. What are renin inhibitors used for?The most common approved indication of renin inhibitors are Hypertension. For more information, please click on the image below to log in and search. How to obtain the latest development progress of renin inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of renin inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与占吉仑相关的药物交易

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